A 7 month old female infant presented with persistent jaundice since 2 weeks of life, high colored urine, and normal colored stools. On examination, she had deep icterus, hepatomegaly, and failure to thrive. Initial tests showed conjugated hyperbilirubinemia. Further workup included normal thyroid function, urine tests, TORCH titers, and alpha-1 antitrypsin level. Liver function tests showed elevated enzymes. Imaging showed hepatomegaly. Differentials included genetic and infectious causes of neonatal cholestasis.

1. APPROACH TO CHILD
WITH CHOLESTASIS
Presented By:-
Dr. Rizwan Gouri
Moderator:-
Col. Vandana Negi
1

2. History
 07 month old female infant
 2nd product of non consanguineous marriage
 R/O Leh
 Informant : Mother
 Reliability: Fair
2

3. History
 Brought by parents with c/o-
 Persistent jaundice since day 15 of life.
 Failure to thrive
 Developmental delay as compared to peer
group
3

4. Obstetrical history
 Born to P2002 mother
 Mother ’s blood group ‘AB’ +ve
 HBsAg, HIV, VDRL, TORCH serology - Negative
 1st child is 7 yr old male alive & well
 2nd spontaneous conception
 Booked & supervised at SNM Hospital Leh
4

5. Obstetrical history
 No H/o
 Fever with rash
 Gestational Diabetes , Gestational Hypertension
 UTI, Prolonged Rupture Of Membranes
 Jaundice during antenatal period
 Delivered at SNM Hospital Leh at term
normally with B.Wt of 2.7 Kgs
5

6. Postnatal history
 Passed meconium within 24 hours of birth
 Developed neonatal jaundice on day 03 of life,
recovered with PT
 Day 15 of life re-admitted at SNM with increasing
jaundice
 Urine -high colored, stools - yellow in color
6

7.  No H/O:-
 Acholic stool
 Constipation
 Lethargy, Irritability, Seizures
 Poor feeding
 Prolonged bleeding
 Vomiting
7
Postnatal…

8. Postnatal…
 At 02 month of age Child was admitted at 153
GH and transferred to CH(WC)
 Taken to PGIMER Chandigarh, where child was
investigated
 No h/o hepatotoxic drug intake
 Immunization – Up to date
8

9. Developmental History
07 month
 Gross motor-
 Rolls over
 Not able to sit with support, crawl
 Fine motor-
 Grasps and transfers objects
 Social
 Displays stranger anxiety
 Language
 No babbling
9

10. 10

11. Substrate
(per day)
Amount
Energy
(k calorie)
Protien
(gm)
Breast milk 600 ml 402 6.6
Fresubin 15 gm 66 2.5
Cerelac 15 gm 60 2.5
Total 528(-122) 11.6(-3.4)
• Calorie requirement of this child (100+50 k calorie/kg/day)
= 150 x5 = 750 k calorie/per day
• Protein requirement : 3 gm/kg/day = 5x3 = 15 gm/kg/day
•Exclusively breast fed along with supplements till 06 months
Dietary History
11

12. Questions
12

13. History…
 Consanguinity
 ABO Rh of mother
 HbsAg , HIV, VDRL, TORCH serology of mother
 UTI, PROM
 Cholestasis in mother
 Birth weight of the neonate
 Passage of meconium within 24 hours
 Colour of the urine and stool
 Source of nutrition
13

14. History …
History/ Specific question Implication
Similar problem in siblings ,
parents or family members
Genetic disease with AR/AD inheritance
Consanguinity AR Inheritance
Maternal infection TORCH infections ,HBV infection
Cholestasis of pregnancy May be seen in PFIC
ABO Rh Rh, ABO isoimmunization
Birth weight SGA supports IU Infection ,against BA
Neonatal sepsis, UTI Sepsis induced cholestasis
Feeding Hist & h/o Weight gain IU Infections/ IEM
Vomiting , constipation, IEM /CHPS/ hypothyroidism
Lethargic/ Irritable Hypothyroidism/ IEM
High coloured urine Conjugated hyperbilirubinemia
Clay coloured stools Cholestasis , EHBA
14

15. Summary
 Term female infant
 Persistent jaundice since 02 weeks of life
 High colored urine
 Normal coloured stools with N stooling pattern
 Developmental delay
 Failure to thrive
15

16. Possibilities
16

17. Diff dx of jaundice in childhood
17

18. Examination
18

19. O/E- (PGI Chandigarh at
03 months of age)
 Wt- 3.2 Kgs (+500 Grams) (N- +1500Gms)
 OFC-37 cms (0.5 Cm/ week) ( +6 Cms)
 HR-126/min
 Temp-Afebrile
 Icterus ++
 No cyanosis, pallor, clubbing, LA, pedal edema
19

20. Examination …
 S/E- Abdomen
 Soft distended, umbilicus centrally placed
 Liver 2 cms, below RCM, Liver span 6 cms, firm
smooth regular margin
 Spleen- 2.5 cms below left costal margin.
 Other S/E-
 CVS,CNS, R/S-WNL
20

21. EXAMINATION: [AH(R&R)]
07 months
 Child is active, alert & oriented to mother
 Weight- 5.000 Kg (7.450 kg) < 3rd percentile
 OFC- 40 cm (44 cm) < 3rd percentile
 Length-58 Cms (66.10 cms) < 3rd percentile
21

22.  HR-108/min (90-120/min)
 RR-30/min (30-40/min)
 Temp-Afebrile
 Icterus++ up to soles
 No dysmorphic features
EXAMINATION: [AH(R&R)]
22

23. Examination
 Pallor
 Edema Nil
 Patechie
 No cataract, No K-F Ring
 No embryotoxon
23

24. High coloured urine
24

25. Clay coloured stools
25

26. Examination of Stool Colour
26

27.  Abdomen-
 Distended, umblicus centrally placed, small
umblical hernia
 No visible vein seen over abdomen
 Liver 3.5 cm below right costal margin, span- 7cm
 Spleen 3cm below left costal margin
 No Lump, No ascites
Systemic Ex…
27

28. 28

29. Systemic Ex…
 CNS
 Child is fully conscious
 No evidence of encephalopathy
 No seizures
 No focal deficit
 CVS
 Respiratory System
NAD
29

30. Dysmorphic features
Cardiac Murmur
Sick Infant
Umblical hernia, Constipation
Midfacial defects,Micropenis
Cataracts
Situs Inversus, Polysplenia
Chorioretinitis, Embryotoxon
Abdominal Mass
Cutaneous Haemangioma
Clinical Clues
30

31. Dysmorphic features Trisomies, Alagilles
Cardiac Murmur Alagilles
Sick Infant Sepsis, cong infection, IEM
Umblical hernia, Constipation Hypothyroidism
Midfacial defects,Micropenis Septo optic dysplasia
Cataracts Galactosaemia, IU Infections
Situs Inversus, Polysplenia EHBA
Chorioretinitis, Embryotoxon TORCHS, SOD, Alagilles
Abdominal Mass Choledochal Cyst
Cutaneous Haemangioma Liver Haemangioma
Clinical Clues
31

32. Physical examination
Alagille’s Syndrome
 Dysmorphic features
 Prominent forehead
 Deep set eyes
 Pointed chin
 Bulbous tip of nose
 Evidence of heart disease
 Butterfly vertebrae
 Posterior embryotoxon
32

33. Butterfly vertebrae
Embryotoxon
33

34. Trisomy 21, 13 ,18
34

35. Neonate with hypothyroidism
35

36. Summary
Term female infant with persistent jaundice since 02 weeks
of life, passage of high colored urine, normal coloured
stools with normal stooling pattern . Child has
developmental delay and failure to thrive.
On examination- Deeply icteric with hepatoplenomagaly.
36

37. Possibilities
37

38. Diff dx of jaundice in childhood
38

39. (38%)
(04%)
(38%)
(64%)
(58%)
(08%)
(04%)
(02%)
(35%)
(53%)
(18%)
TORCH Infections (42%)
(06%)
(04%)
(07%)
suspected(33%)
(02%)
(09%)
Others (19%)
Etiology of 1008
cases of neonatal
Cholestasis :
Combined data of 8
Medical centers in
India
(IAP Book Of
Pediatric
Gastroenterology)
(12%)
39

40. Prolonged jaundice
 Step 1: Confirm cholestasis
 Step 2: Identify a treatable cause
 Step 3: Recognise complications
 Step 4: Early referral to specialist unit when
necessary

41. 41
Initial Tests Rationale
Total & direct bilirubin Elevated direct fraction confirms
cholestasis
AST, ALT, S.alb, coagulation profile Hepatocellular injury, severity of hepatic
dysfunction
Thyroid Profile Hpothyroidism
Septic screen,Urinalysis & urine culture Sepsis &UTI can cause cholestasis in
neonates
TORCH Titers IU infections
GALT assay, urinary succinylacetone Galactosemia , Tyrosinemia
USG abdomen, HIDA Biliary atresia, choledochal cyst
Alpha-1 Antitrypsin level Alpha-1 antitrypsin deficiency
Serum amino acids Aminoacidopathies
Urine organic acids Zellweger syndrome, lysosomal disorder
IRT ,Sweat chloride/CF TR mutation Cystic fibrosis
S.Bile acid measurement Confirms cholestasis, might indicate
inborn error of bile acid biosynthesis

42. Hemogram
(AT PGI Chandigarh)
Date TLC Hb
(g/dl)
Reticulo-
cytes(%)
PBF
25/09/2012 10700(P34L61M04E01) 8.6 1.2
Moderate Microcytic
Hypochromic with few
macrocytes &
occasional eliptocytes
27/09/2012 9200(P53L38M04E03) 9.0 - -
30/09/2012 5200(P26L64M06E03) 9.5 - -
Normal
Value
1 month – 1 year
6000 – 17500
2 mon – 6 mon
11.5 – 15.5
42
Blood group – B ‘+ve’

43. Serum Biochemistry (AT PGI Chandigarh)
Date 25 Sep 12 28 Sep 12
Bilrubin (T-0-1.0) (C-0-0.3mg%) T-21.76,C-15.61 T-20.96,C-17.36
Total Protein (4.6-7.4 g%) 5.6 6.2
S.Albumin(3.9-5g%) 3.2 3.9
AST (U/L) (15-55) 58 90
ALT (U/L) (5-45) 379 457
Serum Alkaline Phos (0-250) - 1500
PT - C-12,T-13
INR - 1.08
BUN (7-19mg%) 6 -
S.Creat (0.3 –0.7mg%) 0.3 0.4
Na+ (38 - 145mEq/L) 145 -
K+ (3.5 - 6mEq/L) 4.7 -
Cl- (97-110mEq/L) 103 -
Ca+ (8.8 – 10.8mg%) 8.79 9.9
Ip (3.8-6.5mg%) 4.4 -
43

44. Hemogram [AT AH(R&R)]
Date 27/01/13
Hb 11.3 gm/dl
TLC 8400cells/cmm P-28
L-57
PLT 2,30,000/cmm
Date 04/02/13
Hb 11.8 gm/dl
TLC 10,400cells/cmm P-84
L-10
PLT 2,03,00cells/cmm
Normal Value
TLC :1 mon – 1 yr
6000 - 17500
Hb : 11.5 – 15.5
g/dL
44

45. Coagulation profile
Date 15/01/2013 23/01/2013 4/2/2013
PT T-15.8, C-13.0 T-14.2, C-13.0 T-14.2, C-13.0
INR 1.29 1.12 1.23
45

46. Serum Biochemistry [AT AH(R&R)]
Date 27/01/2013 04/2/2013 15/02/2013
S. Bilrubin (T-0-1.0) (C-0-
0.3mg%)
T-17.7, C-10.5 T-31.2, C-22.0 T-21.8, C-11.7
ALT (15-55U/L) 349 1098 420
AST (U/L) (5-45) 114 425 116
Alkaline Phosphatase 1110 1387 1447
GGT (8-90IU/L) 48 - 36
Total Protein(4.6-7.4g%) 5.3 - 6.1
S.Albumin (3.9-5g%) 3.4 - 3.6
BUN (7-19mg%) 10 0.6 8
S.Creat (0.3 – 0.7mg%) 0.3 0.2 0.2
Na+ (138 - 145mEq/L) 139 136 140
K+ (mEq/L) (3.5 - 6) 4.2 5 4.4
46

47. INV…
 Thyroid profile – Normal
 URINE RE/ME- WNL
 Urine for
 Reducing substances
 Urinary succinylacetone
 Urine Culture- Sterile
-ve
47

48. Neonatal Cholestasis
 Prolonged neonatal jaundice
[Jaundice that last longer than 14 days (term) or 21
days (premature babies)]
 Conjugated hyperbilirubinemia
 Conjugated bilirubin >1mg/dL if TB < 5mg/dL
 >20% Total Bilirubin if TB is >5 mg/dL
 High coloured urine with or without acholic stools
 Occurs in 1:2500 live births
48

49. Alpha 1 Antitrypsin
123 mg/dl (90.00-200.00)
[24/09/2012]
G6PD 2.00 U/g of Hb (>2.00)
Cystic Fibrosis (IRT) 21.40 ng/ml B (<70.00)
Other investigation
49

50. Investigations …
 TMS
 GCMS
 GALT
 Blood Ammonia
 S. Lactate
 TORCH Serology
 Markers Of Hepatitis A,B,C
Normal
Negative

51. Investigations
 USG Abdomen- Normal Scan
 UGI Endoscopy - Normal
 ANA, Anti LKM , Anti Sm antibodies - Negative
51

52. Triangular cord sign
52

54. Choledochal Cyst
54

55. HIDA scan
 PGI Chandigarh: Date- (09/10/2012)
 Impaired heparocytes function with N bilio-enteric
drainage
 AH(R&R): Date- (21/01/2013)
 The scan findings are suggestive of poor heptocellular
function. However there is no evidence of biliary
obstruction seen.
55

56. Evidence based
 Role of HIDA Scan:
 Almost 100% sensitive, but has poor specificity for
billiary atresia.
 Excretion of tracer into the small bowel, almost
always excludes billiary atresia
 But, non-draining scan is not specific, may have
many different aetiologies such as neonatal
hepatitis & interlobular duct paucity.
Gilmour SM, Hershkop M, Reifen R, Gilday D, Roberts EA. Outcome of
hepatobiliary scanning in neonatal hepatitis syndrome. J Nucl Med 1997;
38:1279-82.
56

57. CONJUGATED HYPERBILIRUBINAEMIA
(direct/total bilirubin > or = 20%)
CLOTTING SCREEN
Normal Deranged
1mg vitamin K
i.v.
Repeat clotting studies after 4
hours
Stabilise infant:
Assess airway , breathing and
circulation
Broad Spectrum antibiotics
Regular Vit K iv
N-acetyl- cysteine
100mcg/kg/24 hours
Ranitidine iv
Save urine & serum (especially
if transfusing)
Blood if Hb <8
Platelets if count <20
FFP 10mls/kg if bleeding
Examine stools
Pigmented Acholic/Pale
EXCLUDE FOLLOWING:
Infective
Haematological
Inborn errors of metabolism
Parenteral nutrition
Endocrinopathy
Storage disorders
Genetic/Familial
Vascular
Idiopathic
Severe Cholestatic Liver
Disease
Urgently Exclude
Biliary Atresia
Derangement persists
YES
*Age <6 weeks
Kasai
portoenterostomy
*Age > 6 weeks
liver
transplantation
NO

58. 58

59. 59

60. Summary
 Term neonate with persistent jaundice since 02 weeks of
life, passage of high colored urine,
Normal coloured stools with N stooling pattern .
Developmental delay and failure to thrive. Deeply icteric
with hepatoplenomagaly.
 Conjugated hyperbilirubinemia, Deranged LFT, N- GGT,
HIDA S/O hepatoellular dysfunction. Coagulation profile
-N, IEM, IUI work up, markers of Hepatitis A,B,C&
workup for autoimmune hepatitis - Negative.
60

61. Diff dx of jaundice in childhood
61

62. LIVER BIOPSY
B/529/13

63. H & E 10X

64. H & E 40X
H & E 20X

65. H & E 40X

66. H & E 20X

67. H & E 20X

68. Reticulin stain

69. PAS –D STAIN

70. PERL’S STAIN 20X

71. HPE diagnosis
 Precirrhotic liver disease with periportal
hepatitis and cholestasis was opined

72. DIFFERENTIALS
 Alfa 1 antitrypsin deficiency
 PFIC
Further workup :
 Biochemistry
 Electron microscopy
 Genetic analysis

73. condition
Investigation
α 1 antitrypsin
deficiency
Progressive
Familial
Intrahepatic
Cholestasis
Bile salt
synthetic
defects
Idiopathic
neonatal
hepatitis
α 1 antitrypsin Low Normal Normal Normal
GGT Elevated Normal Normal Elevated
S. Bile acids - Elevated Low -
Biliary bile acids - Low - -
Dignosis Liver biopsy , PI
phenotype
Genetic
studies for
defective
FIC1,BSEP,
MDR 2 proteins
Fast Atom
Bombardmen
t –Mass
Spectrometry
-
Liver biopsy ++ + + +
73
DIFFERENTIALS

74.  Progressive Familial Intrahepatic
Cholestasis
 Bile acid synthetic defects
 Idiopathic neonatal hepatitis
 α 1 antitrypsin deficiency
74
DIFFERENTIALS

75. PFIC
Disease Clinical features Investigation
Common to all: Intense pruritus, jaundice, nutritional deficiencies of fat and
water soluble vitamins
Type –I Systemic involvement : liver ,
pancreases
Diarrhea
Normal GGT, granular bile,
paucity of interlobular bile
duct
Type-II Liver involvement, overlap
with Type I
Normal GGT,
Giant cell hepatitis, canalicular
and hepatocellular cholestasis
Type-III Delayed until early adulthood
H/O cholestasis of pregnancy
in mother
Markedly elevated GGT
Liver biopsy may mimic biliary
atresia
75

76. PFIC1 PFIC2 PFIC3
Transmission AR AR AR
Chromosome 18q21-22 2q24 7q21
Gene ATP8B1/F1C1 ABCB11/BSEP ABCB4/MDR3
Protein FIC1 BSEP MDR3
Location
/expression
Hepatocyte,
colon,intestine,apical
membranes
Hepatocyte
canalicular
membrane
Hepatocyte
canalicular
membrane
Biochemical
features
N GGT, high serum &
low biliary bile acids
N GGT, high serum &
low biliary bile acids
High GGT, N biliary
bile acids,low –
absent biliary PC
Treatment Biliary diversion, LT Biliary diversion, LT UDCA if residual
PC,LT
Prognosis Cirrhosis by end of 1st
decade ,LT around 2nd
decade
Require LT in 1st
decade
Variable
76
PFIC

77. PC
Hepatocyte
OCT
NTCP OATP
OC
BA OA
MDR2/
3
OA
MRP2
BSEP
BA
FIC1
MDR
1PS
Cholangiocyte
Cl-
AQP
BA
ASBT
AECl-
HCO3
-
H2O
CFTR
Cl-
Bile
flowPL
Ch
ABCG5/8
MRPsOSTα/β
Transport Regulators

78. Treatment of specific cause of
NH
 Bacterial infections, congenital syphilis,
toxoplasmosis,malaria require therapy
 Metabolic disorders like galactosemia requires
withdrawal of milk and milk products
 Other metabolic disorders treat accordingly
 HRT for Hypothyroidism
78

79. Medical Mx of Cholestasis
79

80. For future
 Genetic counseling
 Antenatal diagnosis for metabolic disorders
 Specific treatment from day one of life
80

81. Management
 Breast feeding
 Complementary feeds with MCT oil
 Water & fat soluble vitamins as
recommended
81

82. Present Status
 Weight: 5.3 Kgs.
 OFC: 41 cms
 Length: 63 cms.
All < 3rd percentile
82

83. Take home message
 Aggressively work-up neonatal cholestasis
 Early identification of cause cholestatic jaundice
enable optimal timing of medical and surgical
management.
 Pale Colour Stool : almost ALWAYS warrant further
investigations.
83

84. Thank you